Obesity is a major public health problem due to the increase in obesity-related chronic diseases such as type 2 diabetes. The development of obesity-related insulin resistance and type 2 diabetes can be linked to dysregulation of the ability of adipose tissue to adequately store energy in the form of triglycerides, leading to ectopc lipid accumulation in non-adipose tissues. The nuclear hormone receptor peroxisome proliferation-activated receptor gamma (PPAR?) in adipocytes is a key factor in integrating lipid metabolism with glucose homeostasis and insulin sensitivity. Activation of PPAR? by the thiazolidinedione (TZD) class of anti-diabetic drugs is associated with expansion of the adipose tissue and enhanced ability of the adipose tissue to store dietary lipids. These drugs alter PPAR? activity and PPAR? protein levels, an indication that understanding the link between PPAR? activity and PPAR? protein stability may offer new insights into how obesity contributes to NIDDM. PPAR? stability in adipocytes is regulated by enzymes of the ubiquitin proteasome pathway, a highly selective signaling pathway that targets proteins to the proteasome by tagging the protein with multiple ubiquitin polypeptides. Using siRNA-based screening, we identified a ubiquitin ligase, Siah2 that regulates PPAR? protein levels and PPAR? activity in adipocytes. Our preliminary studies using a Siah2KO mouse model show Siah2 regulates PPAR? protein levels and inflammation in adipose tissue and that eliminating Siah2 prevents obesity-related insulin resistance. We hypothesize that Siah2-dependent regulation of PPAR? activity links obesity with adipose tissue inflammation and insulin resistance. Our goal is to provide mechanistic insight into the role of Siah2 in controlling the relationship between PPAR? protein levels, insulin sensitivity and inflammation in adipose tissue. In Specific Aim 1, we will test the hypothesis that Siah2-dependent modification of PPAR? limits PPAR? activity by increasing ligand-dependent proteasomal degradation of PPAR?. Specific aim 2 will assess the effect of Siah2 on adipose tissue inflammation. In specific aim 3, we will test the hypothesis that Siah2 in adipocytes regulates systemic insulin sensitivity via regulation of PPAR? activity and lipid partitioning between adipose and non-adipose tissue. Together, these studies will provide new insight into the relationship between PPAR? activity and the role of adipose tissue in regulating insulin sensitivity and will advance our goal of determining if the ubiquitin-proteasome system represents a novel therapeutic target in the treatment of obesity-related insulin resistance and type 2 diabetes.